The sensitivity of the substantia nigra to MPTP induced toxicity is believed to result from two unique characteristics: 1) dopamine uptake and 2) presence of neuromelanin. Melanin is known to bind both MPTP and its metabolite MPP+. Chloroquine blocks this binding and so inhibits the Parkinson-like syndrome in monkeys given MPTP. However, a direct link between toxicity and binding has not been provided. We have developed a model to show this relation. We have found that a clonal variant (Blad) of the B 16 melanoma cell line synthesizes melanin, binds more MPTP and is more sensitive to it than B 16 cells, which contain very little melanin. When the melanin content of B 16 cells is raised by melanocyte stimulating hormone (MSH), they bind more (3H)MPTP and are more sensitive to MPTP-induced toxicity. There is excellent correlation between MSH concentration, melanin content, the amount of (3H)MPTP binding to the cell and the level of sensitivity. Thus, melanin plays a crucial role in the sensitivity of melanoma cells to MPTP. The replacement of neurotransmitter deficient brain areas by a cell line rather than fetal tissue is being explored. PC-12 cells remain differentiated as neuron like cells when exposed to nerve growth factor (NGF), provided that the NGF is replenished. We have confirmed work by others in demonstrating that mitogenesis of PC- 12 cells is halted and they extend neurites after ras sarcoma viral infection without the need of an exogenous supply of NGF. We now find that these cells exhibit a higher level of acetyl- cholinesterase activity and a greater norepinepherine uptake mechanism than noninfected cells. Dopaminergic metabolism, release and ultrastructural features are under study.